Amphoteric amino aldehydes reroute the Aza-Michael reaction

Article abstract of DOI:10.1021/ja9072194

(Chemical Equation Presented) Amphoteric amino aldehydes, which exist as stable dimers, participate in an aza-Michael/aldol domino reaction with α,β-unsaturated aldehydes to afford stable 1,5-aminohydroxyaldehydes in high yields and diastereoselectivies.

Full text of DOI:10.1021/ja9072194

Published on Web 10/26/2009
Amphoteric Amino Aldehydes Reroute the Aza-Michael Reaction
Ryan Hili and Andrei K. Yudin*
DaVenport Research Laboratories, Department of Chemistry, UniVersity of Toronto, 80 St. George Street,
Toronto, Ontario, Canada M5S 3H6
Received September 2, 2009; E-mail: ayudin@chem.utoronto.ca
Scheme 1. General Scheme for a Domino Aza-Michael/Aldol
A kinetically stable molecule containing both nucleophilic and
electrophilic nodes constitutes an amphoteric entity.1 Such mol-
ecules are of significant interest, as their participation in both
reversible and irreversible polar reactions can offer a wide palette
of bond-forming options. While the opposing nucleophilic and
electrophilic centers render such molecules capable of forging
multiple bonds in a single transformation, it is the orthogonality
between these centers that ensures high chemoselectivity.2 Although
a limited number of amphoteric molecules are known, their synthetic
value is substantial, most notably because of their participation in
multicomponent and domino processes.3 Two of the widely used
multicomponent processes, the Passerini and Ugi reactions, hinge
upon the isocyanide functional group. Isocyanides can be viewed
as (1,1) amphoteric molecules because the same atom (the R-carbon)
establishes a connection with both the nucleophile (carboxylic acid)
and electrophile (aldehyde or imine). Our continuing efforts to
expand the scope of synthetically useful amphoteric molecules have
led us to examine systems in which the electrophilic and nucleo-
philic nodes of reactivity are separated by one or more atoms. Of
particular interest are (1,3) systems, exemplified by the unprotected
R-amino aldehydes in which NH aziridine, a well-established
precursor to complex amines, plays an integral role.4 When
employed as electrophiles in the Pictet-Spengler process, ampho-
teric aziridine aldehydes have enabled nucleophilic interception of
the electrophilic iminium ion intermediate. As a result, a novel
reaction pathway has been established.4a A notable feature char-
acterizing this domino process is the initiation step, which is
triggered by nucleophilic attack at the aldehyde center. This
nucleophile-initiated process represents only half of the reaction
dichotomy characterizing amphoteric molecules. The reactivity
profile can be reduced into two canonical representations: a
nucleophile-initiated mechanism and an electrophile-initiated mech-
anism (Figure 1).
Reaction
While the general pathway of a domino hetero-Michael/aldol
process has been demonstrated elsewhere,5 we recognized that our
system presented some notable differences. Particularly important
is the fact that amphoteric amino aldehydes exist as stable dimers,
with the equilibrium strongly favoring the dimeric species in a
variety of solvents (Scheme 2). We recently established that collapse
of the hemiacetal of the dimer to yield the acyclic dimer is
kinetically slow.6 It was important to determine whether similar
rate-limiting kinetics might be operative during an aza-Michael/
aldol reaction.
Scheme 2. Amphoteric Amino Aldehydes: Dimer/Monomer
Equilibrium
When 2a was reacted with methyl acrylate in acetonitrile at 40
°C, only the rather uninteresting aza-Michael adduct containing the
undissociated dimer was isolated (Scheme 3, R ) i-Bu). This
apparent lack of monomeric aldehyde reactivity contrasts that
observed during thio- or oxa-Michael/aldol reactions involving thio
or hydroxyl ketones, which also exist in dimeric form.5b As opposed
to the sluggish kinetics governing the dissociation of R-amino
aldehyde dimers, the R-thio ketone dimers readily dissociate,
conferring favorable kinetics onto thio-Michael/aldol domino
reactions.
We hypothesized that this difference in dissociation kinetics
might provide an opportunity to establish a previously inaccessible
pathway in domino aza-Michael/aldol reactions. While fast dimer
dissociation would produce an intermediate capable of undergoing
a conventional 5-(enolendo)-exo-trig cyclization,7 slow dimer
dissociation might present the possibility of an 8-(enolendo)-exo-
trig pathway, whereby aldol addition occurs prior to dimer
dissociation (Scheme 3).
To increase the chemoselectivity of the aldolization step, we
focused on reaction conditions that increase the rate of the aldol
cyclization while decreasing the rate of dimer dissociation. Since
dimer dissociation is slow in polar aprotic solvents, we chose to
react aziridine aldehyde dimer 1a with cinnamaldehyde 2a in
acetonitrile using a secondary amine8/Brønsted acid catalyst
combination (Table 1). Gratifyingly, aminohydroxyaldehyde 3a was
Figure 1. Amphoteric molecules and their reactivity profiles.
We sought to determine the feasibility of an electrophile-initiated
domino process. Our initial efforts focused on investigating reactions
between amphoteric amino aldehydes and Michael acceptors
(Scheme 1).
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C O M M U N I C A T I O N S
Scheme 3. Influence of Dimer Dissociation Kinetics on Reaction
Outcome
Benzoic acid was necessary to promote the reaction; its absence
resulted in less than 30% conversion over a 48 h period. Stronger
acids such as HCl and trifluoroacetic acid resulted in decreased
yields and byproduct formation, while reactions catalyzed by acetic
acid were sluggish. The substrate scope of substituted cinnamal-
dehydes 2 shows that the reaction tolerates both electron-donating
and electron-withdrawing substituents on the aromatic ring, with
all cases delivering high yields and diastereoselectivities (Table 1).
Substrates containing electron-donating groups required longer
reaction times, whereas those with electron-withdrawing substituents
were found to react with efficiencies comparable to that of
cinnamaldehyde.
A solvent screen established acetonitrile as the most effective
medium. Other aprotic solvents delivered reduced yields and longer
reaction times, while protic solvents such as trifluoroethanol (TFE)
resulted in quantitative recovery of the starting material. Interest-
ingly, our earlier studies identified TFE as the only medium in which
appreciable levels of monomeric amino aldehyde were formed. One
could expect the 5-(enolexo)-trig aldol pathway to operate on the
monomeric species (Scheme 3). However, the only reaction seen
in TFE was that between pyrrolidine and amino aldehyde dimer 1
(Scheme 4), with no evidence for the 5-(enolexo)-trig pathway. The
5-(enolexo)-trig pathway is also not likely to be responsible for
product formation in MeCN, as the product would have had to be
formed through collapse of the bicyclic aziridine intermediate
(Scheme 5). As 5-endo-trig addition of the aziridine to the R,ꢀ-
unsaturated system in 3 is unlikely because of orthogonal orbital
geometries, so too is the microscopic reverse of the process,
rendering the 5-exo-trig pathway highly improbable. It therefore
appears that the monomeric aziridine aldehyde is not the reactive
aza-Michael donor.
isolated in >20:1 diastereoselectivity and 89% yield. No byproducts
from the 5-(enolendo)-exo-trig cyclization pathway were observed.
Table 1. Scope of the Aza-Michael/Aldol Reactiona
Scheme 4. Catalyst Consumption through Hemiaminal Ether
Formation
Scheme 5. The 5-Exo-Trig Pathway Is Inoperative
In contrast to TFE, aprotic solvents such as MeCN disfavor dimer
dissociation but preclude the sequestration of pyrrolidine, thus
creating a possibility to control the aziridine aldehyde equilibrium.
We believe that this is precisely what is behind the observed reaction
outcome. Importantly, in situ analysis of the reaction mixture using
electrospray ionization mass spectrometry showed the production
of an adduct between 2a and aldehyde prior to product formation,
suggesting that aza-Michael addition of the dimer to the R,ꢀ-
unsaturated aldehyde occurs before dimer dissociation. This
observation supports a reaction pathway operating through the
mechanism defined in Scheme 6. Upon iminium activation, aza-
Michael addition of the dimer to the R,ꢀ-unsaturated aldehyde
affords aza-Michael adduct 4, which, following hemiacetal collapse,
undergoes an intramolecular 8-(enolendo)-exo-trig aldolization to
afford intermediate 6. Transformation of 6 into 7 is expected to be
straightforward, driven by the excellent leaving-group ability of
protonated aziridine (pKaH ) 8.0 in water). Hydrolysis of the
enamine and elimination of monomeric aziridine aldehyde gives
the product aminohydroxyaldehyde 8. The monomeric amino
a Reaction conditions: 0.2 mmol of 1a-c, 0.4 mmol of 2, 20 mol %
pyrrolidine/benzoic acid, 0.25 M in MeCN, room temperature. b Product
identities were determined using 1D and 2D 1H and 13C NMR
spectroscopy and high-resolution mass spectrometry (HRMS). c dr was
determined by crude 1H NMR analysis; % yield is of purified product.
d
1
E/Z ratio was determined by crude H NMR analysis.
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C O M M U N I C A T I O N S
Scheme 6. Proposed Mechanism for the Aza-Michael/8-Exo-Trig
Aldol Reaction
mode of reactivity was demonstrated through a novel aza-Michael/
aldol pathway, which furnished aminohydroxy R,ꢀ-unsaturated
aldehydes in high yields and with excellent diastereocontrol. These
products cannot be easily accessed by the conventional Baylis-
Hillman reaction because of the substitution pattern of the olefin.
We also note that the products contain unprotected amine func-
tionality. The overall reaction efficiency has been attributed to
solvent-dependent control over the dissociation kinetics of aziridine
aldehyde dimers. Disfavoring dimer dissociation directs the aza-
Michael/aldol domino process toward a novel 8-(enolendo)-exo-
trig cyclization. The products of this reaction are significant in that
they extend the orthogonal amine/aldehyde relationship to (1,5)
systems. As opposed to the (1,3) systems, the (1,5) variants are
not dimeric, but one can anticipate their participation in a range of
nucleophile- and electrophile-initated processes, delivering useful
templates for complex amine synthesis via aziridine ring opening.
As reversible dimerization is a salient feature of aziridine aldehydes,
our study should facilitate investigations aimed at probing the
reaction dichotomy of amphoteric molecules and synthesis of
complex chiral amines.
Acknowledgment. We thank NSERC for financial support.
Supporting Information Available: Experimental procedures and
chemical characterizations of compounds 3a-j (1H and 13C NMR and
HRMS). This material is available free of charge via the Internet at
http://pubs.acs.org.
aldehyde rapidly redimerizes and re-enters the reaction, which is
why the reaction stoichiometry is 1:1.9a
The high diastereoselectivity of this process is likely a result of
the rigid stereochemical environment assumed by the dimeric
intermediate 5 (Scheme 6).9b To better understand the origin of
the selectivity for the intramolecular aldol addition, an ab initio
computation at the Hartree-Fock level of theory was used to locate
the transition state for the process (Figure 2). The transition state
exhibits an intramolecular hydrogen bond between the aldehyde
oxygen and the hemiaminal hydrogen, which governs the facial
selectivity for enamine attack on the aldehyde. This transition state
assembly correctly predicts the observed diastereoselectivity.
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Figure 2. Intramolecular aldolization of 5. The calculated transition state
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